DE2941288A1 - CYSTEIN DERIVATIVES - Google Patents

Description

SANTEN PHARMACEUTICAL CO. LTD., Osaka / Japan Cysteine derivatives

description

The invention provides (1) compounds of the formula

CH ₃
I.

CH ₃ -C-CONHCHCOOh II
SR ¹ CH ₂ SR ²

1 2
wherein R or R is lower alkanoyl, benzoyl, lower alkyl or lower alkyl substituted by carboxy; either R or R can be hydrogen; and its physiologically acceptable salts, (2) a composition comprising a compound of formula (I) and / or a physiologically acceptable salt thereof and a pharmaceutically acceptable excipient, (3) a method for suppressing liver disorders in mammals the administration of an effective dose of a compound of the formula (I) or a physiologically acceptable salt thereof, and (4) a process for the preparation of a compound of the formula (I). The above lower-alkanoyl and lower- alkyl radicals contain 1 to 6 carbon atoms.

The compounds of this invention are useful as drugs for suppression of hepatic disorders due to its effect of removing free radicals.

Under cysteine ai e- of the formula (I) are whether-

1 2 is equal to the compounds in which R and R are hydrogen atoms, are as sputum-dissolving compounds well known, the derivatives in which R and R substituent groups represent novel compounds, and their effect with respect to the suppression of liver disorders and the reduction of blood pressure and its anti-rheumatic effects are newly discovered facts.

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Processes for the preparation of the derivatives of the formula (I) are generally divided into the following two methods (i) and (ii):

Method (i):

CH ₃

CH3-C-CONHCECOOH (ID

i I

SH CH ₂ SH

The compounds of the invention can be obtained by adding the compound of formula (II) and either carboxylic acids or a halide of the formula R -Y (III) [where R is the

1 2

has the same meaning as for R or R in dPr formula (I) was indicated, and Y denotes hydroxyl or halogen] by conventional methods such as the Schotten-Bauman reaction, in which they are reacted in water, organic solvents or solvent mixtures of the above two, or the mixed acid anhydride method.

Method (ii):

The compounds of the invention can be obtained by one compound of the formula

CH ₃
I.

R ¹ -SC-COY (IV)

I.
CH ₃

in which R or Y has the same meaning as indicated in the formula (I) or (III), and cysteine in a manner analogous to implemented in method (i).

The compounds obtained in the aforementioned methods (i) and (ii) (I) are reacted with desired bases, and as a result, salts of the compounds (I), which are known proven to be medicinal products. Such bases are sodium hydroxide, sodium carbonate, potassium hydroxide,

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2941238

Ammonium hydroxide, calcium carbonate, ^ triethylamine, benzylamine, Triäthanolar.Jn, Ν, Ν-dimethylethylenediamine, piperidine, N-ethylpiperidine, Morpholine, N-ethylmorpholine etc.

Since the compounds (I) according to the invention have an asymmetric If they have carbon atoms, they are steromers. All of the same are included in the category of compounds according to the invention.

The following examples illustrate the preparation of the compounds (I).

example 1

S-acetyl-N- (S-acetyl -2-mercapto-2-methylpropanoyl) -L-cysteine

11.2 g (0.05 mol) of N- (Z-mercapto-2-methylpropanoyl) -L-cysteine are dissolved in 250 ml of potassium carbonate and 15.7 g ^{are added dropwise with stirring and under a nitrogen atmosphere at 0 ° C.} (0.2 mol) of acetyl chloride. After the addition, the mixture is stirred for 1 hour at room temperature and acidified with 6N hydrochloric acid. The oil formed is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated to dryness in vacuo to give 10.7 g (69.6%) S-acetyl-N-2-mercapto-2-methylpropanoyl) -L-cysteine. F - 131-132 ° C (benzene). Ca] ^ ⁷ -30.3 ° (c = 1.3, methanol).

Example 2 S-Benzoyl-N- (S-benzoyl-2-mercapto-2-methylpropanoyl) -L-cysteine

11.2 g (0.05 mol) of N- (2-mercapto-2-methylpropanoyl) -L-cysteine are dissolved in 200 ml of potassium carbonate and 21.1 g are slowly added dropwise at 0 ° C. with stirring and under a nitrogen atmosphere (0.15 mol) of benzoyl chloride. After the addition, the mixture is stirred for 1 hour at room temperature and acidified with 6N hydrochloric acid. The oil formed is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated to dryness under reduced pressure to give 9.7 g (45 %) of S-benzoyl-N- (S-benzoyl-2-mercapto-2-methylpropanoyl) -L-cysteine . F = 127.5-128.5 ° C (ethyl acetate).

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2S41288

- 7-31.3 "(c = 1.4, methanol).

Analysis (C _{? 1} H "

Calculated: C 58.45 H 4.90 N 3.25% Found: 58.28 4.85 3.24 %

IR spectrum (Nujol): 3260, 1730, 1659, 1622, 907, 894 cm " ¹

Example 3 S-pivaloyl-N- (S-pivaloyl-2-mercapto-2-methylpropanoyl) -L-cysteine

11.2 g (0.05 mol) of N- (2-merca ^ to-2-methylpropanoyl) -L-cysteine are dissolved in 50 ml of η-sodium hydroxide and ^{17 are added dropwise at 0} ° C. with stirring and under a nitrogen atmosphere, 0 g (0.13 mol) of pivaloyl chloride and 150 ml of aqueous n-sodium hydroxide are added. After the addition, the mixture is stirred for 1 hour at room temperature and acidified with 6N hydrochloric acid. The oil formed is extracted with ethyl acetate and the organic layer washed with water, dried and concentrated to dryness under reduced pressure to give 3.2 g (16.4 %) of S-pivaloyl-N- (S-pivaloyl-2-mercapto- 2-methylpropanoyl) -L-cysteine. F = 140-141 ⁰ C (ethyl acetate-petrol). Ca] ^ ⁷ -30.0 ° (c = 1.4, methanol).

night & glow changed

Analysis (C ₁₇ H ₂₉₅ ^

Calculated: C 52.15 H 7.47 N 3.58
Found: 52.23 7.55 3.57%

IR spectrum (Nujol): 3370, 1732, 1685, 1648, 941 cm " ¹

Example 4 S-pivaloyl-N- (2-mercapto-2-methylpropanoyl) -L-cysteine

11.2 g (0.05 mol) of N- (2-mercapto-2-methylpropanoyl) -L-cysteine are dissolved in 50 ml of η-sodium hydroxide and then add 6.6 g dropwise with stirring and under a nitrogen atmosphere at 0 ° C (0.055 mol) of pivaloyl chloride and 60 ml of η-sodium hydroxide. After the addition, the mixture is kept at room temperature for 1 hour

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stirred and acidified with 6N hydrochloric acid. The oil formed will extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness 11.5 g (75.0%) S-pivaloyl-N- (2-mercapto-2-methylpropanoyl) -

27 D

L-cysteine to yield. M.p. 115-117 ° C (benzene). Ca] ^ ⁷ -25.7 ° (c = 1.1, methanol).

Analysis (C ₁₂ H ₂₁ NO ₄ S ₂ ):

Calculated: C 46.88 H 6.88 N 4.56%
Found: 46.54 6.93 4.49 %

IR spectrum (Nujol): 3335, 1743, 1687, 1625 cm " ¹

Example 5

S-carboxymethyl-N- (2-carboxymethylthio-2-methylpropanoyl) - O ^ L-cysteine

Dissolve 11. 2 g (0.05 mol) of N- (2-mercapto-2-methylpropanoyl) -

L-cysteine InWm potassium carbonate and adds 11.3 g (0.12 mol) of monochloroacetic acid and 1.0 g of potassium iodide. The mixture is stirred overnight at room temperature under a nitrogen atmosphere and acidified with 6N hydrochloric acid. Sodium chloride is added and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried and concentrated to dryness to give 16.5 g (97.2 %) of S-carboxymethyl-N- (2-carboxymethylthio-2-methylpropanoyl) -L-cysteine. Ca] _D -39.5 ° (c - 2.0, methanol).

IR spectrum (neat): 1720, 1630, 1260, 1180 cm " ¹

Example 6 S-methyl-N-C2-methyl-2- (methylthio) propanoyl] -L-cysteine

11.2 g of N- (2-mercapto-2-methylpropanoyl) -L-cysteine are dissolved in 75 ml of 2m potassium carbonate and 17.0 g of methyl iodide are added with stirring to. The mixture is stirred for 1 hour at room temperature and then acidified with hydrochloric acid. The obtained crystals are separated by filtration and obtaining

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dried from 9.44 g (75.1%) S-methyl-N- [2-methyl-2- (methylthio) propanoyl] -L-cysteine. F = 120.5-5121 ° C (ethanol-n-hexane). Ca] ¹⁹ -19.3 ° (c = 0.7, methanol).

IR spectrum (Nujol): 3335, 1735, 1725, 1620 cm " ¹

Nuclear Magnetic Resonance Spectrum _{(CDCl 3} , ppm): 1.53 (6H, s), 2.10 (3H, s), 2.15

(3H, s), 3.02 (2H, d, J = 6 Hz), 4.55-4.90 (IH, m), 7.87 (IH, d, J = 8 Hz), 11.15 (IH, s)

Example 7 N- [2-Methy1-2- (methylthio) propanoyl] -L-cysteine

7.1 g of L-cysteine are dissolved in 88 ml of 2m potassium carbonate and 7.5 g of 2-methyl-2- (methylthio) propanoyl chloride [boiling point 78 ° C. (37 ° C.) ^{are added dropwise with stirring and under a nitrogen atmosphere at 0 ° C.} mm Hg)]. After the addition, the mixture is stirred at room temperature overnight. The mixture is acidified with hydrochloric acid and the resulting crystals are separated by filtration and dried to obtain 10.4 g (89.8% of the title compound. F = 110.5-112 ° C (ethyl acetate). [Α] ¹⁹ + 7.4 ° (c = 1.1, methanol).

IR spectrum (Nujol): 3350, 1730, 1620 cm " ¹

Nuclear Magnetic Resonance Spectrum _{(CDCl 3} , ppm): 1.46 (IH, t, J = 9 Hz), 1.53 (6H, s),

2.10 (3H, s), 2.93-3.20 (2H, m), 4.66-4.95 (IH, m), 7.93 (IH, d, J «8 Hz), 10.40 (IH, s)

The suppressive effect of the compounds in liver disorders can be tracked by looking at liver disorders Compounds administered to animals and the suppressive effects of the compounds in experimentally induced liver disorders examined. Among the active substances that cause experimental liver disorders are carbon tetrachloride, Thioacetamide, bromobenzene, paracetamol, D-galactosamine etc. Im it is assumed that with carbon tetrachloride

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caused liver disorders, the cytochrome P-450 breaks the carbon-chlorine bond to form free Rc.cicals (CC1 ·) with high toxicity that lead to disorders where they combine with thiol groups of the proteins of the liver cell membrane or the lipid peroxidation reaction of the membrane promote [Biochem. Pharmacol., 2 ±, 49 (19 72); _25_, 2163 (19 76)].

The invention was made to show the suppressive effect in liver disorders to study using carbon tetrachloride as an active ingredient leading to experimental liver disorders, and the suppressive effect of the compounds of the present invention on liver disorders was examined using of serum transaminase (s-GOT and s-GPT) as an indication.

The compounds used in the experiments were as follows :

Compound A: S-acetyl-N- (S-acetyl-2-mercapto-2-methylpropanoy1) -L-cysteine

Compound B: S-pivaloyl-N- (S-pivaloyl-2-mercapto-2-methylpropanoyl) -L-cysteine

Compound C: S-Benzoyl-N- (S-benzoyl-2-mercapto-2-methylpropanoyl) -L-cysteine

Pharmacological studies

Male Wistar rats were kept with a body weight of 170-200 g, each group of 5 rats, 16 hours without food and then put them to the experiments a. 100 mg of the compounds A to C were administered orally per 1 kg of body weight. 0.25 m / af carbon tetrachloride was injected intraperitoneally per 1 kg body weight (5 ml per 1 Ic body weight in the form of an olive oil solution) for 30 minutes Administration of each compound. As a control, 5 ml of olive oil were administered intraperitoneally per 1 kg of body weight. The serum transaminase was measured 24 hours after the administration of carbon tetrachloride is determined. The results are in the given in the table below.

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ORIGlHAL INSPECTED

- li -

Tabel Effect of the compounds on serum transaminase

^ S ^ Serum
N ^ transaminase Serum GOT Ver
ratio serum GPT Connection ^ v Jugs -
Unit / ml (100) Karmen—
Unit / ml Ver
ratio no
(Control) 1042813118 (59.8) 2025 * 550 (100) Connection A 6236 ± 234 (70.2) 1656 ± 423 (80.9) Connection B 7320 ± 822 (55.7) 18251171 (90.1) Compound C 5806 ± 1152 1445 ± 207 (70.6)

Each value represents the mean i S.D. for 5 rats.

As can be seen from the table, it was found that the serum transaminase was suppressed by administration of Compounds A to C.

As is clear from the above pharmacological test, the compounds (I) of the invention are useful as medicaments useful for suppressing liver disorders, and it is too assume that they act as anti-rheumatic agents. When administered for a.itirheumatic purposes, the compounds may be combined with thiol compounds as commonly used at present, depending on the cases. the Compounds of the invention are effective when used in any oral or parenteral routes of administration, and may be in any drug form for oral or parenteral administration may be prescribed depending on the particular need.

For oral administration, they can be prescribed in the form of tablets, capsules, granules, etc. and are used pharma

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zeutisch made by making the connections with at least an excipient such as lactose, starch, sucrose, etc., furthermore, in the preparation of these drug forms additives other than the above-mentioned excipients can be used, such as disintegrators and wrapping materials as well as lubricants (magnesium stearate etc.) and binders (Dextrin).

Medicaments to be administered parenterally can be in any form of sterilized aqueous or non-aqueous isotonic solution. Isotonicity adjuvants, preservatives, solubilizers and stabilizers can also be added to these drugs.

Although the amount of the compounds of the present invention in each composition can be appropriately changed, it should be determined so that an appropriate dose can be obtained. The dose varies depending on the desired therapeutic effect, the route of administration, the patient to be treated, the duration of treatment, etc. In general, in order to achieve the desired effect, it is desirable to use a dose of 0.2-20 mg of the compounds of the invention each To administer 1 kg of the patient's body weight per day. In adults, this can be achieved by unit dosage forms containing 50 to 300 mg of the compounds of the invention include, administered 1-3 times a day.

The following examples explain the medicaments containing the compounds according to the invention as active ingredients

(a) tablet form

Compound B 100 mg

Lactose 100 mg

crystalline cellulose 40 mg

Carboxymethyl cellulose 7 mg

Magnesium stearate 3 mg

a total of 250 mg

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· '■ Λ

(b) Granular form

Compound A 100 mg

Polyvinylpyrrolidone 25 mg

Lactose 305 mg

Hydroxypropyl cellulose 50 mg

Talc 10 mg

total 490 mg

(c) powder form

Compound C 300 mg

Lactose 230 mg

Strength 440 mg

colloidal silicon dioxide 30 mg

total 1000 mg

(d) capsule shape

Compound A 50 mg

Lactose 82 mg

crystalline cellulose 56 mg

colloidal silicon dioxide 2 mg

a total of 190 mg

(e) Injection form

There are 1 to 100 mg of compound A in the form of the sodium salt in 1 ml of an aqueous solution with a pH from 5.0 to 7.0.

030018/0732 ORIGINAL

Claims (14)

Dr. F. Zumstein Sr. - Dr. E. Assmann - Dr. R. Koenigsberger Dipi.-Phys. R. Holzbauer - Diel.-Ing. F Klinc ^ iron - Dr. F. Zumstein jun. tN 'ANWÄLTE SOOO Munich S BrauhausstraQo 4 Telephone Collective No. 22 53 41 Telegrams Zumpal ■ Telex 529979 14/90 / N Case SAN-Il patent claims 1. S-substituted derivatives of N- (2-mercapto-2-methylpro panoyl) -cysteine of the formula CH3-C-CONHCHCOOH
I!
SR ¹ CH ₂ SR ² 1 and their physiologically acceptable salts, in which R and R are straight-chain or branched C 1 -C ₆ -alkanoyl, benzoyl, C 1 -C 4 -alkyl or C 1 -C 4 -alkyl, substituted by carboxy; and wherein either R or R can be hydrogen. 1 2 2. Compounds according to claim 1, wherein R and R acetyl, Mean pivaloyl, benzoyl, methyl or carboxymethyl. 1 2 3. Compounds according to claim 1, wherein either R or R Means hydrogen. 4. S-acetyl-N- (S-acetyl-2-mercapto-2-methylpropanoyl) -L-cysteine. 5. S-Benzoyl-N- (S-benzoyl ^ -mercapto ^ -methylpropanoyl) L-cyscein. 6 • S-pivaloyl-N- (S-pivaloyl ^ -mercapto ^ -methylpropanoyl) L-cysteine. 7. N- (2-Mercapto-2-methylpropanoyl) -S-pivaloyl-L-cysteine. 8. S-methyl-N- [2-methyl-2- (methylthio) propanoyl] -L-cysteine. 9. N- [2-Methyl-2- (methylthio) propanoyl] -L-cysteine. 10. S-carboxymethyl-N- (2-03 ^ 0X1 ^^ 1 ^ 1 ^ 10-2 propanoyl) -L-cysteine. 030018/0732 OMQtNAL INSPECTED 11 · Composition containing a compound according to claim in an amount sufficient to suppress liver disorders, as well as a pharmaceutically acceptable excipient. 12. A method for the suppression of liver disorders in mammals, characterized in that an effective dose of a compound administered according to Claim. 1 13. Process for the preparation of an S-substituted derivative of N- (2-mercapto-2-methylpropanoyl) -cysteine of the formula CH ₃
I. CH ₃ -C-CONHCKCOOh (I) 1 I.
SR ¹ CH ₂ SR ² characterized in that a compound of the formula CH ₃
I. CH ₃ -C-CONHCHCOOh (II) i I
SH CH ₂ SH with a carboxylic acid, an acid halide or an alkyl halide of the formula R -Y (III) in which IT, K ² or R ^{5 is} C ₁ -C ₆ -alkanoyl, benzoyl, C ^ -Cg-alkyl or C ₁ -C ₆ - Alkyl substituted by carboxy; either R or R can be hydrogen; Y is hydroxy or halogen. 14. Process for the preparation of an S-substituted derivative of N- (2-mercapto-2-methylpropanoyl) -cysteine of the formula CH ₃
I. CH ₃ -C-COMHCHCOOH II
SR ¹ CH ₂ -SH characterized in that a compound of the formula 0300 1 8/0732 7941238 CH ₃ I. R ¹ -SC-COY (IV) I.
CH ₃ reacts with cysteine, where R is C ^ -C ^ alkanoyl, benzoyl, or C.-Cg-alkyl, substituted by carboxy, and Y is halogen or hydroxy. 030018/0732